1. Field of the invention
The present invention relates to a pharmaceutical composition containing cyclosporin. More specifically, the present invention relates to a pharmaceutical composition containing cyclosporin, an oil component, a hydrophilic cosurfactant consisting of propylene carbonate or a mixture of propylene carbonate and polyoxyethylene-polyoxypropylene block copolymer, and a surfactant. The composition of the present invention is characterized in that it can be dispersed in an external phase such as water, artificial gastric juice and intestinal juice, etc. to form it self-emulsion with mild stirring and therefore, by appropriately adjusting the constitutional ratio of each component the diameter of particles in the inner phase of the emulsion thus formed can be readily controlled to 100 nm or below.
2. Background Art
Cyclosporin is a high molecular peptide compound (molecular weight 1202) consisting of 11 amino acids and has a potent immunosuppressive activity by inhibition of growth and differentiation of T cells. Therefore, cyclosporin has been used for suppression of immunological rejection of the patients, which may be caused by organ and tissue transplantation, for example, transplantation of kidney, liver, heart, bone marrow, pancreas, skin, cornea, etc. In addition, cyclosporin has also been used for suppression of autoimmune diseases, especially inflammatory diseases such as rheumatoid arthritis.
Cyclosporin has a unique structure in which among 11 amino acids 7 amino acids are in the N-methylated form. In addition, cyclosporin, having a cyclic, symmetric structure, has a very low polarity and therefore, is very slightly soluble in water (0.04 mg/ml H.sub.2 O, 25.degree. C.). Due to such a low water-solubility of cyclosporin, the bioavailability of cyclosporin is as very low as 30% or less. In addition, the absorption of such insoluble compound may be greatly influenced by bile juice secretion and fat amount in food. In the case of cyclosporin, it has been reported that the difference of absorption between each individual is as very great as about 5-50%.
When cyclosporin is administered, 10 to 27% of the absorbed drug is subjected to the first pass effect in liver and the distribution half-life is 0.7 to 1.7 hour and the excretion half-life is 6.2 to 23.9 hours. Such pharmacokinetic parameters of cyclosporin show a great variation between each individuals depending on secretion of bile juice, condition of patient and kind of transplanted organs. In addition, cyclosporin has a very low therapeutic index and frequently shows renal toxicity as the typical side effect. That is, cyclosporin shows renal side effects such as reduction of glomerular filtration, increase in proximal renal tubular reabsorption, etc. A form of chronic progressive cyclosporin-associated nephrotoxicity is characterized by serial deterioration in renal function and morphologic changes in the kidney. Therefore, in U.S.A. cyclosporin is classified as a group of drugs which should be subjected to a periodic therapeutic drug monitoring (TDM).
Since cyclosporin has such specific properties, that is, a very slight solubility, a low bioavailability and a great variation in absorption between each individual, a great dosage unit and a narrow therapeutic index, and the unstable patient condition to be treated with cyclosporin, it is very difficult to establish the optimum drug dosage regimen for survival of transplanted patient by maintanance of efficient and constant blood concentration which can avoid side effects and rejection. Accordingly, numerous studies have been extensively conducted to develop an improved pharmaceutical formulation. Such study of pharmaceutical formulation has been mainly concentrated on the means which can solubilize cyclosporin. Typical example of such means includes the use of liposome, microsphere, the mixed solvent system consisting of general vegetable oil and surfactant, etc., the formation of powdery composition using adsorption, inclusion complex, solid dispersion, etc., and the other numerous formulations.
The oral preparation containing cyclosporin as the main active ingredient has been commercialized in the form of a solution or soft capsule. Recently, the microemulsion preconcentrate composition containing cyclosporin has also been formulated and commercialized in the form of soft capsule.
The microemulsion has been firstly reported by J. H. Schulman in 1943 and mainly studied as the carrier for cosmetic application. General microemulsion is a thermally stable and optically transparent preparation comprising two or more immiscible systems formed by surfactants and has some advantages that it has very low surface tension and small particle size to show high absorption and permeation properties. However, since the formation of microemulsion requires more surfactant than that used for formation of general emulsion, when the microemulsion is administered or applied for a long period, the mucosal irritation to be caused by each component must be considered. Therefore, in medical field the microemulsion has been utilized only in the field of preparations which is applied to the skin in a short period, for example, preparation for hair, detergent, etc.
According to the optimum water-in-oil microemulsion disclosed in U.S. Ser. No. 818,965, it is described that when the microemulsion is prepared by selecting the surfactant and the cosurfactant which is more hydrophilic than the surfactant, and then adding the surfactant and the oil component to the external phase in which the cosurfactant is dissolved, the transparent microemulsion can be efficiently obtained under more stable and variable conditions. In addition, this patent also reports the microemulsion preconcentrate formulation which is prepared by a method that the very slightly soluble drug is dissolved in hydrophilic cosurfactant such as small chain hydrocarbons and then the oil solution produced by mixing the drug solution as prepared above with oil component and surfactant is added to the external phase to form the microemulsion.
In the case of cyclosporin as the very slightly soluble drug, U.S. Pat. No. 4,388,307 discloses the oral liquid preparation prepared by using oil, surfactant and ethanol as the hydrophilic solvent. This preparation is in the form of microemulsion preconcentrate and therefore, before it is administered per oral, it must be diluted with water. Accordingly, it is very difficult to adapt the subject patient to its administration and to control the accurate dosage and as a result, it is impossible to actually apply to the patient who must receive the cyclosporin therapy during his all life since it is uncomfortable to carry.
In order to improve such disadvantages involved in the liquid preparation, it has been proposed that the microemulsion preconcentrate is formulated in the form of soft capsule. However, in case of the cyclosporin soft capsule containing ethanol as hydrophilic component, this capsule preparation must contain a large amount of ethanol for sufficient solubilization of cyclosporin. However, since ethanol permeates the gelatin shell of the capsule to volatilize even at normal temperature, the content of ethanol is reduced in course of time. As a result, when the capsule preparation is stored at high temperature or at normal temperature for long period, the crystallization of cyclosporin may be caused. Thus, the change in constitutional ratio of the composition caused by the change of ethanol content and the crystallization of cyclosporin result in a great variation in the bioavailability of cyclosporin and therefore, it is impossible to obtain the reliable uniform therapeutic effect. In this condition, in an effort to prevent the volatilization of ethanol from the soft capsule preparations during storage, the soft capsule preparations are packed in a special packaging material, such as aluminum-aluminum blister package. However, such special packaging does not completely prevent the change of ethanol content in course of time. Therefore, this also results in a great variation in bioavailability of cyclosporin and may contribute to the manufacturing price increase.
To improve the above-mentioned disadvantages of the use of ethanol as hydrophilic cosurfactant a method using non-ethanol component as hydrophilic cosurfactant has also been proposed. U.S. Pat. No. 5,342,625 discloses the soft capsule preparation formulated from microemulsion concentrate which solves the above-mentioned problems. In this patent, a pharmaceutical composition in the form of microemulsion concentrate in which a pharmaceutically acceptable C.sub.1-5 alkyl or tetrahydrofurfuryl di- or partial-ether of low molecular mono- or poly-oxy-alkanediol, for example, diethyleneglycol monoethyl ether [e.g. Transcutol] or tetrahydrofurfurylalcohol polyethylene glycol [e.g. Glycofurol], or 1,2-propylene glycol is used as a hydrophilic cosurfactant and ethanol is used as a hydrophilic co-solvent is disclosed. However, all the hydrophilic cosurfactants used in this patent are glycols having the alcoholic group (--OH) in their structure.
Since such --OH group containing glycols are very hygroscopic, they absorb moisture present in atmosphere and further have a high permeability to gelatin shell. Therefore, it is very difficult to formulate the composition containing such glycolic cosurfactant into the soft capsule preparation. Particularly, in encapsulating and drying procedures during the preparation of soft capsules water present in the capsule shell is absorbed into the capsule contents by 20% of the amount of the hygroscopic solvent to cause the change in constitutional ratio of the composition and then in drying procedure water is distributed again into the gelatin shell together with the constituents of the composition and volatilized through the outer capsule shell. According to this, the composition of this patent has disadvantages that the initial constitutional ratio of the composition is greatly changed to cause the change in the appearance of the preparation and also the decrease in production yield.
Furthermore, since the solvent used in the above U.S. patent has it softening effect on gelatin shell, in view of the pharmaceutical formulation this composition also has the problem that the stability of appearance of the gelatin capsule is greatly reduced. Such problem is more serious when the solvent is those used also as the plasticizer for gelatin, for example, propylene glycol or glycerin. For this reason, the use of propylene glycol as the main solvent is almost impossible. Specifically, propylene glycol is used generally by approximately 5% of the capsule contents and may be used by approximately 10% together with a hardening agent for gelatin shell at the most. When the content of propylene glycol is over 10%, the stability of appearance of the gelatin shell is greatly affected.
As one method for improving such disadvantages, Korean Patent Application No. 94-13945 discloses a cyclosporin soft capsule composition (trade name: Neoplanta.RTM.) using dimethylisosorbide as a hydrophilic cosurfactant. In this patent, it is described that since dimethylisosorbide used as the hydrophilic solvent has substantially no permeability to the gelatin shell in comparison to the hydrophilic cosurfactants used in the prior art, the soft capsule preparation using dimethylisosorbide provides some advantages that it does not show the change in appearance of the capsule and content of the ingredients.
Dimethylisosorbide is commercialized under trade name Arlasolve.RTM. and its chemical name is 1,4:3,6-dianhydro-2,5-dimethyl-D-glucitol. It is a solvent which has been generally used as a percutaneous absorption promoting agent only in the field of topical pharmaceutical ointment or cosmetics such as lotions.
As mentioned above, the conventional microemulsion composition requires more surfactant than the general emulsion and therefore, in the case of drug which is continuously administered to the patient during his whole life after transplantation, for example, cyclosporin, the toxicity due to long term administration of solvent and surfactant used in the preparation of microemulsion must be considered. In this connection, the LD.sub.50 value of each surfactant used in cyclosporin formulations in the prior art is as follows: dimethylisosorbide 5.63 ml/kg (rat, per oral), Cremophor RH40&gt;16 g/kg (rat, per oral), Glycofurol 3.5 ml /kg (mouse, intravenous injection) and propylene glycol 21-33.7 g/kg (rat, per oral). In case of the organic solvent of which the toxicity has been relatively well known, the LD.sub.50 value of each solvent is as follows: acetonitrile 3.8 g/kg (rat, per oral), acetone 10.7 ml/kg (rat, per oral), benzene 3.8 ml/kg (rat, per oral), toluene 7.53 g/kg (rat, per oral), isopropanol 5.8 g/kg (rat, per oral), butanol 4.36 g/kg (rat, per oral), and propylene carbonate, which is used in the present invention as the solvent, 29 g/kg. In considering the LD.sub.50 values as above, the toxicity of dimethylisosorbide is relatively high as much as the toxicity of general organic solvents and therefore, it is expected that the long term administration of the composition containing dimethylisosorbide per oral may cause some problems. Furthermore, according to this patent dimethylisosorbide is used in an amount 4 times as much as cyclosporin on the basis of weight. This must be seriously considered in view of the fact that this drug is administered to the patient through his whole life.
In addition, in case of the cyclosporin soft capsule composition using dimethylisosorbide, it is disadvantageous that obtain the comparable drug absorption to the commercial product Sandimmun Neoral.RTM. and the solubilizing effect sufficient to prevent the precipitation of cyclosporin the solvent is used in a relatively larger amount than the active ingredient. This means an increase in the unit dosage. That is, the hydrophilic cosurfactant, i.e. dimethylisosorbide is used in the 4 times amount per unit weight of cyclosporin. Therefore, the total weight of the unit dosage form of Neoplanta.RTM. capsule containing 100 mg of cyclosporin is about 1270 mg which is about 1.2 times as much as the weight of unit dosage form of the prior formulation (Sandimmun Neoral.RTM.). In addition, the price of dimethylisosorbide is 20 to 30 times as high as the price of solvents used in the prior art to cause an increase in the manufacturing cost of the preparation and the price of drug.
Thus, the present inventors have studied numerous cyclosporin preparations using various hydrophilic cosurfactants, oils and surfactants in view of their stability and bioavailability to prepare the cyclosporin-containing composition which makes up for various disadvantages involved in the pharmaceutical preparations of the prior art and is suitable for the formulation into the soft capsule and to establish the reliable drug dosage regimen with low toxicity and small dosage unit. As a result, we have identified that when as the hydrophilic cosurfactant in the cyclosporin-containing composition propylene carbonate, which is a pharmaceutically acceptable solvent, or a mixture of propylene carbonate with polyoxyethylene-polyoxypropylene block copolymer in a liquid state at room temperature is used, the above-mentioned requirement can be satisfied and the disadvantages involved in the prior art preparations can also be improved, and thus completed the present invention.
Accordingly, the object of the present invention is to provide a cyclosporin-containing pharmaceutical composition characterized in that it comprises cyclosporin; propylene carbonate or a mixture of propylene carbonate and polyoxyethylene-polyoxypropylene block copolymer as a hydrophilic cosurfactant; an oil component; and a surfactant.
In addition, another object of the present invention is to provide a soft capsule preparation, a hard gelatin capsule preparation sealed with gelatin bending at the conjugated portion or an oral liquid preparation, prepared from the cyclosporin-containing pharmaceutical composition as defined above.
The foregoing has outlined some of the more pertinent objects of the present invention. These objects should be construed to be merely illustrative of some of the more pertinent features and applications of the invention. Many other beneficial results can be obtained by applying the disclosed invention in a different manner or modifying the invention within the scope of the disclosure. Accordingly, other objects and a more thorough understanding of the invention may be had by referring to the disclosure of invention and the drawings, in addition to the scope of the invention defined by the claims.